Large Meta-Analysis Shows That the Protective Effect Of Pill Use Against Endometrial Cancer Lasts for Decades

First published online:

| DOI: https://doi.org/10.1363/47e6115

Oral contraceptive use has an established protective effect against endometrial cancer, and an analysis pooling data from "almost all" of the relevant epidemiological studies shows that the effect is long-lasting.1 According to results of the meta-analysis, the risk of endometrial cancer is lowered by 24% for every five years of pill use, and the reduction in risk persists for more than 30 years after use is discontinued. The researchers estimate that in high-income countries, 10 years of oral contraceptive use lowers the cumulative risk of endometrial cancer by age 75 from 2.3 per 100 women to 1.3 per 100.

To explore the association between oral contraceptive use and endometrial cancer risk, researchers requested individual-level data from the principal investigators on relevant epidemiological studies. Studies were eligible for inclusion if they collected information about hormonal ­contraceptive use and reproductive history among women who developed any type of cancer of the uterus and had previously not had cancer (except nonmelanoma skin cancer). A total of 44 eligible studies were identified, and 36 are included in the pooled analysis. (The remaining research groups declined to participate or agreed to provide data at a later date.) The researchers used conditional logistic regression to assess the association between oral contraceptive use and endometrial cancer risk, and they fitted a log-linear trend across categories of duration of use to estimate the relative risk of cancer per five years of use. They estimated cumulative incidence rates of endometrial cancer up to age 75 on the basis of relative risk estimates and age-specific incidence rates, and calculated absolute numbers of cancers prevented from birth-cohort–specific prevalences of pill use.

The 36 studies yielded data on 27,276 women with endometrial cancer and 115,743 controls (women with an intact uterus and no previous cancer). Thirty of the studies were conducted in Europe or North America; one was multinational, and the rest were from Asia (three), Australia (one) and South Africa (one). The median year of cancer diagnoses was 2001; women's median age at diagnosis was 63. Thirty-five percent of women with endometrial cancer and 39% of controls had ever used oral contraceptives; the median duration of use was 3.0 years in the former group and 4.4 years in the latter.

Overall, ever-users of the pill had a 31% lower risk of developing endometrial cancer than never-users had; the relative risk was the same in prospective and retrospective studies, but it varied according to tumor type. For every five years of pill use, the risk of endometrial cancer was reduced by 24%; this association was consistent regardless of women's body mass index, parity, use of menopausal hormone therapy, menopausal status, smoking status, age at menarche, ethnicity or alcohol use.

Most women who developed endometrial cancer had discontinued oral contraceptive use many years earlier (median, 29 years), but the median duration of use was longer among women who had last used the pill within the 15 years before diagnosis than among those who had last used it 30 or more years earlier (4.7 vs. 3.0). For any given duration of use, the reduction in risk was slightly greater in more recent users, but it was still significant among women who had last used oral contraceptives 30 or more years before diagnosis.

In high-income countries, the researchers calculate that among never-users of oral contraceptives, 2.3 per 100 women will develop endometrial cancer by age 75. By contrast, the estimated rate is 1.7 per 100 women who use the pill for five years, 1.3 per 100 who use it for 10 years and 1.0 per 100 who use it for 15 years. Between 1965 and 2014, oral contraceptive use prevented an estimated 400,000 cases of endometrial cancer, half of them since 2005.

The researchers acknowledge that it is not possible to be certain that they captured all pertinent studies or to have the most up-to-date information from ongoing ones. The eight studies that they were unable to include in their analyses, they add, contained only a small fraction of women with endometrial cancer; exclusion of these studies therefore "probably had no material effect on the main findings." Meanwhile, the findings were remarkably consistent across the 36 included studies. And the researchers note that while it is unclear exactly how oral contraceptive use protects against endometrial cancer, "it is ­reasonable to infer that the associations recorded here are causal."

D. Hollander


1. Collaborative Group on Epidemiological Studies on Endometrial Cancer, Endometrial cancer and oral contraceptives: an individual participant meta-analysis of 27,276 women with endometrial cancer from 36 epidemiological studies, Lancet Oncology, 2015, doi: 10.1016/S1470-2045(15)00212-0.